Azole derivatives as histamine H3 receptor antagonists, Part 2: C-C and C-S coupled heterocycles

Article abstract of DOI:10.1016/j.bmcl.2010.07.109

With a small series of compounds we demonstrated the variability in the core region of the human histamine H₃ receptor (hH₃R) antagonist structural blueprint by introducing polar azole groups (oxazole, oxadiazole, thiazole and triazole). Additional variations achieved by coupling different residues to the heterocyclic core structure led to further optimisation of in vitro receptor binding of the novel azole derivatives.

Full text of DOI:10.1016/j.bmcl.2010.07.109

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5883–5886
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Azole derivatives as histamine H3 receptor antagonists, Part 2: C–C
and C–S coupled heterocycles
M. Walter a, K. Isensee a, T. Kottke a, X. Ligneau b, J.-C. Camelin b, J.-C. Schwartz b, H. Stark a,
*
a Johann Wolfgang Goethe University, Institute of Pharmaceutical Chemistry, Biozentrum, ZAFES/LiFF/CMP/ICNF, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany
b Bioprojet-Biotech, 4 rue du Chesnay Beauregard, BP 96205, 35762 Saint Grégoire Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
With a small series of compounds we demonstrated the variability in the core region of the human his-
tamine H3 receptor (hH3R) antagonist structural blueprint by introducing polar azole groups (oxazole,
oxadiazole, thiazole and triazole). Additional variations achieved by coupling different residues to the
heterocyclic core structure led to further optimisation of in vitro receptor binding of the novel azole
derivatives.
Received 23 June 2010
Revised 23 July 2010
Accepted 25 July 2010
Available online 1 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
GPCR
Histamine
H3
Pharmacophore
Medicinal chemistry
Bioisosteric replacement
The human histamine H3 receptor (hH3R) is responsible for his-
tamine neurotransmission in the central nervous system (CNS) by
activation of Gai/o-mediated signalling pathways. Due to the
involvement in a multitude of neuronal functions pharmacological
research mainly focuses on the treatment of CNS disorders (e.g.,
schizophrenia, Alzheimer’s disease, epilepsy, narcolepsy) by modu-
lation of the hH3R by antagonists/inverse agonists.1
Western part
1st
Eastern part
Polar group
2nd Basic moiety
Lipophilicresidue
Acidicmoiety
Central
core
Spacer
Basic
A
moiety
The identification of the hH3R in 19832 and the cloning in 19993
led to an enormous interest in the discovery of novel H3R ligands in
both academia and industry. Compound development started with
the preparation of agonists, which all closely resemble the endog-
enous ligand histamine by adopting the imidazole moiety, likewise
the first antagonists. Due to potential drawbacks of the imidazole-
based compounds like reduced brain penetration and interactions
with hepatic cytochrome P450 enzyme systems, non-imidazole
containing ligands were developed.4
Lipophilicresidue
2nd Basic moiety
Carbonylgroup
Hetero-
cycle
A‘
N
A = linking element; A‘ = CH2, S
Although the number of structural classes is continuously ris-
ing, almost all hH3R antagonists/inverse agonists follow a general
blueprint, which consists of a basic moiety, mostly a tertiary
amine, linked by a spacer to a central core substituted by a variety
of structural elements providing different physicochemical proper-
ties (Fig. 1).5 The frequently used aromatic core structures1,6 are
not essential for potent binding to the hH3R; even polar groups
are accepted (Fig. 2).7–11
Figure 1. Expanded hH3R antagonist structural blueprint5 and general pharmaco-
phore of presented H3R ligands.
Recently, we successfully introduced polar thiazole groups into
the core region of the structural blueprint.11 The S,N-heterocycle
had a lower impact on receptor binding than its substituents in
the eastern part of the molecule. Enlargement of the molecule by
lipophilic residues (e.g., ST-1025; cf. Fig. 2) and additional basic
moieties were evaluated as major reason for high affine hH3R
ligands. Based on our previous work the aim of this study was
the structural variation of the thiazol-2-yl ether derivatives by
* Corresponding author. Fax: +49 69 79829258.
E-mail address: h.stark@pharmchem.uni-frankfurt.de (H. Stark).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.07.109

5884
M. Walter et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5883–5886
Cl
O
O
O
O
a
b
d
NH3
Br
O
Cl
CH3
Br
N
N
O
O
N
N
1f
1g
1e
Pitolisant (Tiprolisant, BF2.649)8
NNC 3810499
c
H
N
N
O
N
1h
N
N
N
O
1
O
S
O
N
N
Scheme 2. Oxazole synthesis of ligand 1. Reagents and conditions: (a) Br2,
chloroform, 0 °C ? rt, 95%; (b) (i) hexamethylentetramin, chloroform, rt, 12 h; (ii)
HBr, 50 °C, 12 h ? reflux, 1.5 h, 100%; (c) (i) precursor 1d, thionyl chloride,
0 °C ? 60 °C, 2 h; (ii) triethylamine, 4-(dimethylamino)pyridine, 0 °C ? rt, 48 h,
10%; (d) POCl3, 0 °C ? 70 °C, 1.5 h, 75%.
FUB 65410
ST-102511
Cl
Figure 2. Representative hH3R antagonists/inverse agonists.
modification of their linkage to the spacer. Additionally, we intro-
duced new heterocycles containing one to three nitrogen atoms to
extend the variation spectrum of the structural blueprint’s core
element. The eastern part of the molecule was modified by inser-
tion of different lipophilic residues, carbonyl groups or additional
basic moieties as substituents of the heterocycle to obtain further
information on binding behaviour of the derivatives (cf. Fig. 1).
Compounds 1–7 were prepared as shown in Schemes 1–4.
The precursors 5-(piperidin-1-yl)pentanoic acid 1d and
3-(piperidin-1-yl)propyl methanesulfonate 3d were obtained by
reaction of piperidine with methyl 5-chloropentanoate or
3-chloro-1-propanol, respectively, under Williamson-like condi-
tions. The intermediates were further functionalized by alkaline
hydrolysis of the methyl ester structure preparing precursor 1d
or by mesylation with methansulfonyl chloride yielding precursor
3d (Scheme 1).12
H2N
HO
a
b
N
N
N
N
N
N
N
O
N
2a
2
2b
Scheme 3. Oxadiazole synthesis of ligand 2. Reagents and conditions: (a)
NH2OHꢀHCl, EtOH, reflux, 18 h, 3%; (b) (i) precursor 1d, CDI, triethylamine,
acetonitrile, rt, 30 min; (ii) MW, 130 °C, 30 min, 78%.
R1
R2
R1
R2
S
N
S
b
a
S
N
N
S
S
R1
R2
Br
HS
N
N
N
3e-4e
3f-4f
3-4
5
O
O
b
Preparation of compound
1 started with bromination of
HS
acetophenone 1e, followed by Delépine-reaction13 with hexameth-
ylenetetramine to 2-oxo-2-phenylethanaminium bromide 1g. By
reaction with the acid chloride structure, obtained by activation
of precursor 1d with thionyl chloride, a b-ketonamide derivative
was built. Dehydration of the b-ketonamide 1h displayed the last
step of the Robinson–Gabriel oxazole synthesis (Scheme 2).14
Oxadiazole ligand 2 was obtained by reaction of N0-hydroxy-
nicotinamide 2b with precursor 1d, activated by CDI. Derivative
2b was yielded from 3-cyanopyridine 2a and hydroxylamine.15
(Scheme 3).
N
5a
N
O
b
b
N
N
O
N
N
S
S
HS
HS
N
N
N
N
6a
6
7
N
N
N
Nucleophilic substitution reactions led to the C–S-coupled het-
erocyclic compounds 3–7. The 2-bromothiazole derivatives 3e–4e
N
N
NH
N
7a
N
a
Scheme 4. Synthesis of thioether-linked heterocycles 3–7. Reagents and condi-
tions: (a) NaSH, ethanol, reflux, 12–24 h, 75–94%; (b) precursor 3d, K2CO3, DMF, 60–
80 °C, 2–12 h, 13–78%.
Cl
O
NH
N
N
O
CH3
CH3
O
1b
1a
1c
O
O
b
were converted into the mercapto analogues by sodium hydrogen-
sulfide. The mercapto derivatives 3f–4f reacted with mesylate pre-
cursor 3d under basic conditions to compounds 3–4. In the same
way, reactions of the commercially available 2-mercaptoazoles
5a–7a with precursor 3d led to compounds 5–7 (Scheme 4).
All final compounds 1–7 were tested with regard to their
in vitro hH3R binding affinity in a competitive binding assay
(Table 1).8,16
OH
1d
a
Cl
OH
N
OH
NH
3c
3a
3b
c
The introduction of heteroaromatic ring systems containing one
to three nitrogen atoms led to distinct differences in hH3R binding.
Affinities vary from the low nanomolar concentration range to the
complete loss of receptor binding.
The C–C-coupled oxazol and oxadiazol ligands 1 and 2 showed
moderate binding behaviour (Ki values of 63 nM and 110 nM,
O
N
O
S
CH3
3d
O
Scheme 1. Synthesis of precursors 1d and 3d. Reagents and conditions: (a) K2CO3,
KI, acetone, 60 °C, 48–72 h, 70–79%; (b) 6 N KOH, THF/MeOH (3:2), MW, 70 °C,
15 min, 100%; (c) methanesulfonyl chloride, DCM, 0 °C ? rt, 15 min, quantitative.

M. Walter et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5883–5886
5885
Table 1
tration range (Ki values of 110 nM and 187 nM, respectively). The
introduction of a central triazole ring in compound 7 resulted in
a high affine ligand with a Ki value of 18 nM. Most probably, the
incorporation of a further amino function had a higher impact on
this improvement due to beneficial interactions with the receptor’s
binding pocket (Glu206).18 Additionally, the steric enlargement of
the molecule possibly allows positive effects in ligand–receptor
binding.
We successfully introduced polar azole cycles containing one to
three nitrogen atoms into the central core of the hH3R antagonist
structural blueprint. According to our previous work the presented
small series of hH3R ligands emphasised the importance of the
azole substitution pattern and the lower impact of the type of het-
erocycle on receptor binding. Extending the variation spectrum of
the incorporated azoles, the presented ligands enlarge the struc-
ture–activity relationships deduced from the former thiazole series
and indicated again the enlargement of the molecule by lipophilic
(3) and additional basic functions (7) as major reasons for high
affine H3R ligands. As linker between spacer and core element
the thioether moiety resulted to be comparable to the oxyether
of the thiazol-2-yl ether derivatives (compounds 3 and ST-1025).
By introducing different C–C- and C–S-coupled heterocycles we
confirmed the acceptance of polar moieties in the central core of
the structural blueprint. Taken together the results of both series
of azole derivatives we could establish a new structural class of
hH3R ligands containing polar heteroaromatic ring systems as core
element.
In vitro binding affinities of azole derivatives 1–7 to hH3R
N
A
X
R1
Z
Y
R2
Compd
A
X
O
Y
C
Z
R1
R2
Ki hH3Ra (nM)
63
1
CH2
N
H
7
N
2
3
4
CH2
S
N
S
N
C
C
O
N
N
110 17
7.4 1.1
>1000
O
S
S
CH3
CH3
5
6
S
S
O
O
C
N
N
32
5
N
187 15
18 3b
N
N
7
S
N
N
N
N
ST-1025
ST-1093
O
O
S
S
C
C
N
N
11.2 2.1
N
N
20
1
Pitolisant (Tiprolisant, BF2.649)c
2.7 0.5
Acknowledgements
a
[
125I]Iodoproxyfan competitive binding assay on HEK-293 cells stably
expressing hH3R; Kd = 44 pM; values are means SD of one experiment performed
This work was partially supported by the COST action BM0806
‘Recent Advances in Histamine Receptor H4R Research’, the Else
Kröner-Fresenius-Stiftung, and the Hesse LOEWE projects LiFF
and NeFF.
at least in triplicates.
b
[3H]Methylhistamine competitive binding assay on HEK-293 cells stably
expressing hH3R; Kd = 2.98 nM; mean value SD of two independent experiments
performed in duplicates.
c
Ref. 8.
References and notes
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